Small-molecule inhibitors of signal transduction pathways in leukemia therapeutics: how to assess selectivity for malignant signals

Leukemia (2003) 17, 17591761

& 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00www.nature.com/leuCOMMENTARY AND MINI-REVIEWSmall-molecule inhibitors of signal transduction pathways in leukemia therapeutics:

how to assess selectivity for malignant signalsMK White11Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Jefferson Alumni Hall, Philadelphia, PA, USALeukemia (2003) 17, 17591761. doi:10.1038/sj.leu.2403053This invited commentary is addressed to the paper of Shelton

et al1 published in this issue of Leukemia. The intracellular

signaling pathways that control cell proliferation present

attractive targets for the design of therapeutic agents to treat

cancer. In between the growth factor receptors that are found on

the cell surface and the nuclear events that are involved in

regulating cell proliferation and apoptosis, lie two important

signal transduction pathways: the MAPK and the PI3K cascades.

In many cancers, aberrant activation of these pathways can

occur as a result of mutation of a gene encoding a component

signaling protein within the pathway. This leads to constitutive

activation of the protein and a consequent inappropriate

transmission of a continual signal for cell proliferation. For

example, mutation and retroviral capture of the gene encoding

the serine/threonine protein kinase-B also known as c-Akt (PKB/

Akt) in the PI3K pathway produced the oncogene v-akt.

Similarly, mutation and retroviral capture of the kinase c-Raf

in the MAPK cascade produced the oncogene v-raf.Small-molecule inhibitors of the MAPK and PI3K pathways

should, in principle, be able to block the effects of these

oncogenes and thus inhibit cell proliferation and promote

apoptosis of transformed cells. However, there is a problem.

Both the MAPK and PI3K are involved in the regulation of many

cellular processes in normal cells. So how can the therapeutic

potential of small-molecule inhibitors be evaluated relative to

their potentially toxic effects on normal cells? Progress towards

resolving this issue is presented in the paper by Shelton et al1

published in this issue of Leukemia.The research group of James McCubrey at East Carolina

University has elegantly exploited a hematopoietic cell system,

where cell proliferation can be induced either by a physiological

stimulus (the cytokine interleukin-3; IL-3) or by a conditionally

inducible oncogene (of malignant origin). The FDC-P1 cell line

is a mouse hematopoietic cell line that is dependent upon

exogenously added IL-3 or GM-CSF to be able to proliferate in

culture.2...